GDP versus ESHAP Regimen in Relapsed and / or Refractory Hodgkin lymphoma : A Comparison Study

Background: Despite multiple published studies reporting result of salvage regimens for relapsed and refractory Hodgkin’s lymphoma, there are no comparisons of different combinations. Patients and methods: A Total of 44 patients identified with refractory or relapsed Hodgkin’s Lymphoma were considered eligible for this study. The Patients were randomly divided into two groups of 22, one of which were treated with GDP regimen (gemcitabine, dexamethasone and cisplatin) and the other with EHSAP regimen (etoposide, methyl prednisolone, cisplatin and cytarabine) in a prospective manner. The results of each group were compared. Results: There were 27.3% complete response, 31.8% more than 50% response, and 40.9% no response with GDP. ESHAP results were 29.5%, 24% and 45.5%, respectively. Conclusion: There is no significant difference in response rate between GDP and ESHAP regimens as salvage chemotherapy in refractory or relapsed Hodgkin’s Lymphoma.


INTRODUCTION
Treatment of limited stage of Hodgkin lymphoma by introducing new chemotherapy regimens and combining radiotherapy and chemotherapy has significantly evolved in recent years and failure in treatment is seen only in 10 to 20% of patients. 1,2ecently, there are tangible improvements in advanced stages of Hodgkin lymphoma but 10% of patients failed to achieve complete response with combined modality therapy, and 20 to 40% of patients suffered from recurrence or progressive disease. 3,4alvage chemotherapy and autologous bone marrow transplant has become the standard of treatment in recurrence or refractory Hodgkin's Lymphoma. 5,6Different regimens of salvage chemotherapy have been introduced in literature 7- 17 , with the goal of attaining a higher response rate , least side effects, and least damage to bone marrow cells in order to avoid distortion in next phase of treatment which needs mobilization and harvesting stem cells.Considering acceptable progression free survival. 18,19following this treatment, proper chemotherapy before autologous bone marrow transplant is a critical step. 20he two main salvage chemotherapies vastly implemented are GDP (Gemcitabine, Dexamethasone, and Cisplatine) with less hospitalization introduced by Baetz 21 , and ESHAP (etoposid, methyl prednisolone, cisplatine, cytarabine) introduced by Aparicio et al.The latter needs at least five days of hospitalization 22 and has been used as the standard protocol in our Institute over the last few years.Although several studies have been performed to demonstrate the efficacy of these protocols, no comparison has been made between these two treatment regimens. 23,24In order to compare the efficacy of these two protocols, we conducted a randomized prospective clinical trial.In GDP group, one patient suffered from hyperglycemia in the last cycle of treatment and blood sugar was not corrected after termination of treatment.

DISCUSSION
Because achievement to adequate response to salvage chemotherapy before bone morrow transplantation is important this influences transplantation's results and progression free survival of patients.In this study the researcher attempted to compare the results of two methods of treatments: ESHAP vs. GDP .The former has been used as a common treatment regimen at our center over the last few years and needs 5 days of hospitalization.The latter has far less side effects but needs hospitalization.Hospitalization with another method which had acceptable effectiveness with far less side effects and hospitalization required i.e.GDP.Baetz 21 introduced GDP protocol (gemcitabine, dexamethasone, cisplatin) and evaluated patients after 2 cycles of chemotherapy.Among his patients, 4 had complete response, 12 had partial response and 7 had stable disease (without progression on treatment).In the study conducted by Aparicio 22 , 22 patients were treated with ESHAP (etoposid, methyl prednisolone, cisplatin and cytarabine) protocol and were evaluated after 3 cycles of chemotherapy.At the end of the study, 9 patients had complete response and 5 patients had partial response (overall response: 73%).Chemotherapy regimen in GDP group of the current study was slightly different from Baetz 21 study.In this study, patients were hospitalized at least 36 hours in order to hydration in order to reduce the risk of Cisplatin-related nephrotoxicity, while in Baetz 21 study this protocol was prescribed as outpatient and manitol was used in addition to dextrose/saline before cisplatin.Like Baetz study, nephrotoxicity was not seen in the patients in GDP group.Due to lack of response to initial salvage treatment protocol (GDP or EHSAP); cross-over trial was performed in three patients in two groups at the beginning of our study.None of these patients showed response to second-line salvage chemotherapy (either GDP or ESHAP), therefore, this trend was stopped.One of the significant findings was that none of the patients with primary refractory disease responded to protocols used in this study, but all responded to IEV (Ifosfamide, epirubicin, etoposide).None of the patients with recurrent stage IV disease in both groups reached complete response.In Baetz 21 study, 52% of patients treated with GDP protocol had stage III and IV diseases and 48% had stage I and II.In the current study, these rates were 45.5% and 54.5%, respectively.In this study, 13.6% of patients in GDP group had primary refractory disease, while only 26% of patients had primary refractory disease in Baetz study 21 .Compared to Baetz study in which patients received 2 cycles of chemotherapy, in this study patients received 3 cycles of chemotherapy. 21In the current study, overall response rate in GDP group was 54.1%, while it was reported 69.5% in Baetz study. 21n the present study, overall response rate was 50% in ESHAP group, while it was 73% in patients treated with similar protocol in Aparicio study. 22ere, we present the results of comparison on side effects between the two treatment groups and with previous studies (S4, S5): In Aparicio 22 study, 59% of patients developed myelotoxicity (grades III and IV) and one patient died of neutropenic fever, while in the present study side effects were significantly lower and there were no mortality.In Baetzstudy 21 , four patients needed hospitalization, 8.6% were reported to suffer from neutropenia (grade III) and 13% developed thrombocytopenia.In the present study, 4.5% of patients showed grade III neutropenia and 4.5% of patients showed grade I and III thrombocytopenia.Meanwhile, none of the patients needed hospitalization.On this study, there was no significant difference in response rate between the two salvage regimens, but GDP regimen can be used as an outpatient regimen with low toxicity.Based on this study, these two regimens were not suitable options for primary refractory Hodgkin lymphoma as salvage treatment.

CONCLUSION
There is no significant difference in overall response rates between the two protocols but due to least toxicity and lower health care costs result from less hospitalization, GDP could be considered as the better option for salvage regimen.

AKNOWLEDGEMENT
This study was supported by Shiraz University of Medical Sciences (proposal No: 90-5788) and based on Dr. Rezvani's fellowship thesis.
International Journal of Hematology Oncology and Stem Cell Research ijhoscr.tums.ac.ir